Bacterial infections in carrier animals by human pathogens, such as Escherichia coli O157:H7, Campylobacter spp., and Salmonella spp., etc, may be controlled by bacteriophages that attack and kill these bacteria. In order for enteric infections to be controlled with bacteriophages the bacteriophages must be given to animals by mouth in a form that will allow them to act at the site of infection, typically distal to the stomach. Bacteriophage have properties that make preparation of suitable dosage forms difficult. For example, bacteriophages are typically damaged irreversibly by exposure to harsh conditions, by conventional drying techniques and by low pH and proteolysis in the stomach and in the gastrointestinal tract. This damage results from pH-dependent denaturation and proteolytic degration of proteins vital to the viability of the bacteriophage. Bacteriophage represent extremely complicated therapeutics since they are comprised of DNA, or RNA and proteins. Frequently, bacteriophages contain elaborate receptor-binding tail structures that are particularly sensitive to breakage. In essence, our ability to exploit the therapeutic potential of bacteriophages is severely limited by the sensitivity of bacteriophages to low pH, proteolytic degradation and denaturation due to drying, and the lack of suitable methods for preparing economical and effective solid dosage forms.
The therapeutic potential of bacteriophage is described in various reports. In these studies the bacteriophage were used in aqueous form with or without buffers to neutralize stomach acid. These formulations are not ideal because they lack practicality. No methods to produce stabilized, controlled release dosage formulations of bacteriophage have been described.
A bacteriophage delivery system is needed deliver bacteriophage in a controlled manner to enable commercial development of the agents.
Methacrylic acid copolymers (EUDRAGITS™ (methacrylic acid-methyl methacrylate copolymers) have been used extensively to prepare controlled release oral dosage forms of drugs. These polymers have great utility for this purpose because they have been engineered to become soluble in different pH environments. For example, EUDRAGIT (methacrylic acid-methyl methacrylate copolymer) L100 dissolves above pH 5.5 and will protect an active ingredient in acid environments, such as the stomach, yet upon exposure to neutral or basic environments the same dosage form will release the active ingredient. In this regard, the aqueous solubility of the methacrylic acid copolymers is controlled by the degree of protonation of carboxyl groups, which are present on the polymer backbone. If the carboxyl groups are deprotonated, as occurs in basic or neutral environments, the resulting ionic carboxylate groups increase the aqueous solubility of the polymer.
Methacrylic acid copolymers are typically applied to drug-containing cores as thin layers by ladling or spray coating. Alternatively, they may be incorporated into monolithic matrix devices by compression techniques, or by other techniques, such as spray drying. Methacrylic acid copolymers are used generally in the protonated form, either as aqueous dispersions under low pH conditions, or as solutions in organic solvents. Using these conditions has a number of drawbacks. For example, the physical characteristics of the material in dispersion may be detrimental to the drug activity, particularly when it is a biological macromolecule. Similarly, the activity of the drug may be adversely affected by exposure to organic solvents.
Methacrylic acid copolymers have not been used to coat bacteriophages for enteric delivery.